Reply: The associations between hepatic steatosis and incident cardiovascular disease and all-cause mortality
Authors: Heidi S. Ahmed, Michelle T. Long
Journal: Hepatology (2023)

We thank Li et al1 for their interest in our recent article2 studying the association between hepatic steatosis and incident cardiovascular disease (CVD), cancer, and all-cause mortality. We performed multivariable analyses to evaluate the association between CT-derived hepatic steatosis and outcomes and adjusted for CVD risk factors, including diabetes, continuous systolic blood pressure (SBP), alcohol use, current smoking, serum HDL, serum triglycerides, and body mass index. We completed this analysis with both baseline CVD risk factors and time-varying CVD risk factors. As Li and colleagues have pointed out, including time-varying CVD risk factors can complicate the interpretation of the results. There is a bidirectional effect between liver fat and metabolic syndrome—as liver fat worsens, the risk of developing metabolic syndrome increases, and as individuals develop progressive components of metabolic syndrome, the risk of progressive steatohepatitis increases as well.3 In addition, although there are no current Food and Drug Administration–approved medications for the treatment of NASH, several medications used to treat diabetes, including thiazolidinediones and glucagon-like peptide 1 (GLP-1) agonists, are currently being evaluated to reduce steatohepatitis and fibrosis in individuals with NASH.4 We agree that treatment of metabolic syndrome in our cohort may result in possible improvement in steatohepatitis or hepatic fibrosis with changes in downstream systemic inflammation. However, including the changes in these CVD risk factors gives a more accurate evaluation of the participants' real-world risk of CVD, cancer, and mortality, particularly as current treatment approaches overlap. We acknowledge that we are limited by not being able to evaluate the change in liver fat over time in this cohort. In addition, Li and colleagues also highlight that we included multiple CVD risk factors, despite varying impacts on hepatic steatosis and NASH. However, we made this statistical choice as these are known to be associated with incident CVD and are therefore potential confounding variables to the relationship between hepatic steatosis and CVD risk.5 In our study, the major difference using baseline and time-varying CVD risk factors was only in the evaluation of all-cause mortality. Utilizing baseline covariates, hepatic steatosis was associated with all-cause mortality when accounting for all CVD risk factors (HR: 1.21, 1.04–1.40). Although there was a trend toward this association with time-varying CVD risk factors, it was no longer statistically significant (HR: 1.14, 0.95–1.37). This emphasizes that although a diagnosis of hepatic steatosis increases the risk of all-cause mortality, improvement in metabolic syndrome and CVD risk factors may potentially mitigate these outcomes. As this is one of the few studies to include both baseline and time-varying CVD risk factors, future studies utilizing this combination of analysis will be needed to fully understand the impact of hepatic steatosis on CVD, cancer, and mortality risk.